Chemical markup, XML and the World-Wide Web. 3. Toward a signed semantic chemical web of trust.
We describe how a collection of documents expressed in XML-conforming languages such as CML and XHTML can be authenticated and validated against digital signatures which make use of established X.509 certificate technology. These can be associated either with specific nodes in the XML document or with the entire document. We illustrate this with two examples. An entire journal article expressed in XML has its individual components digitally signed by separate authors, and the collection is placed in an envelope and again signed. The second example involves using a software robot agent to acquire a collection of documents from a specified URL, to perform various operations and transformations on the content, including expressing molecules in CML, and to automatically sign the various components and deposit the result in a repository. We argue that these operations can used as components for building what we term an authenticated and semantic chemical web of trust.


Impact of a single eGFR and eGFR-estimating equation on chronic kidney disease reclassification: a cohort study in primary care.
Chronic kidney disease (CKD) is diagnosed using the estimated glomerular filtration rate (eGFR) and the urinary albumin:creatinine ratio (ACR). The eGFR is calculated from serum creatinine levels using the Modification of Diet in Renal Disease (MDRD) or Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations. To compare the performance of one versus two eGFR/ACR measurements, and the impact of equation choice, on CKD diagnosis and classification. Cohort study in primary care in the Thames Valley region of the UK. Data were from 485 participants aged >60 years in the Oxford Renal Cohort Study with at least two eGFR tests. The proportion of study participants diagnosed and classified into different CKD stages using one and two positive tests were compared. Prevalence of CKD diagnosis and classification by CKD stage were compared when eGFR was calculated using MDRD and CKD-EPI equations. Participants included in the analysis had a mean age of 72.1 (±6.8) years and 57.0% were female. Use of a single screening test overestimated the proportion of people with CKD by around 25% no matter which equation was used, compared with the use of two tests. The mean eGFR was 1.4 ml/min/1.73 m2 (95% CI = 1.1 to 1.6) higher using the CKD-EPI equation compared with the MDRD equation. More patients were diagnosed with CKD when using the MDRD equation, compared with the CKD-EPI equation, once (64% versus 63%, respectively) and twice (39% versus 38%, respectively), and 16 individuals, all of who had CKD stages 2 or 3A with MDRD, were reclassified as having a normal urinary ACR when using the CKD-EPI equation. Current guidance to use two eGFR measures to diagnose CKD remains appropriate in an older primary care population to avoid overdiagnosis. A change from MDRD to CKD-EPI equation could result in one in 12 patients with a CKD diagnosis with MDRD no longer having a diagnosis of CKD.


Uncovering the hidden medical curriculum through a pedagogy of discomfort.
What lies beneath the formal or overt curriculum may impair students' professional growth and development, including their ability to foster genuine relationships with patients and others, and may contribute to the inadvertent, often negative attitudes, beliefs, and behaviors expressed by medical students and witnessed by educators within and external to the classroom environment. To understand the impact a hidden medical curriculum has on both students and educators, I look at one particular model often used in medical education--the physician-patient relationship. I show how this therapeutic relationship ought to be understood through a pedagogy of discomfort, a model developed by Megan Boler (Feeling Power; Emotions and Education, 1999), as a way to uncover the hidden curriculum as it engages students in a collective, critical discourse through which their sense of self in relation to others becomes the groundwork for their professional and moral development. Understanding the physician-patient relationship through a pedagogy of discomfort also teachers students how to critically think about the different values and beliefs held by physicians and patients and how to begin to recognize themselves as physicians in relation to their patients and others.


Widening and diversifying the proteome capture by combinatorial peptide ligand libraries via Alcian Blue dye binding.
Combinatorial peptide ligand libraries (CPLLs) tend to bind complex molecules such as dyes due to their aromatic, heterocyclic, hydrophobic, and ionic nature that may affect the protein capture specificity. In this experimental work Alcian Blue 8GX, a positively charged phthalocyanine dye well-known to bind to glycoproteins and to glucosaminoglycans, was adsorbed on a chemically modified CPLL solid phase, and the behavior of the resulting conjugate was then investigated. The control and dye-adsorbed beads were used to harvest the human urinary proteome at physiological pH, this resulting in a grand total of 1151 gene products identified after the capture. Although the Alcian Blue-modified CPLL incremented the total protein capture by 115 species, it particularly enriched some families among the harvested proteins, such as glycoproteins and nucleotide-binding proteins. This study teaches that it is possible, via the two combined harvest mechanisms, to drive the CPLL capture toward the enrichment of specific protein categories.


Shape analysis of vestibular systems in adolescent idiopathic scoliosis using geodesic spectra.
Adolescent Idiopathic Scoliosis (AIS) characterized by the 3D spine deformity affects about 4% schoolchildren worldwide. One of the prominent theories of the etiopathogenesis of AIS was proposed to be the poor postural balance control due to the impaired vestibular function. Thus, the morphometry of the vestibular system (VS) is of great importance for studying AIS. The VS is a genus-3 structure situated in the inner ear and consists of three semicircular canals lying perpendicular to each other. The high-genus topology of the surface poses great challenge for shape analysis. In this work, we propose an effective method to analyze shapes of high-genus surfaces by considering their geodesic spectra. The key is to compute the canonical hyperbolic geodesic loops of the surface, using the Ricci flow method. The Fuchsian group generators are then computed which can be used to determine the geodesic spectra. The geodesic spectra effectively measure shape differences between high-genus surfaces up to the hyperbolic isometry. We applied the proposed algorithm to the VS of 12 normal and 15 AIS subjects. Experimental results show the effectiveness of our algorithm and reveal statistical shape difference in the VS between right-thoracic AIS and normal subjects.


Influence of intermediate and uninterrupted FMR1 CGG expansions in premature ovarian failure manifestation.
Studies attempting to precisely define the range of fragile mental retardation 1 (FMR1) expansions and its inf luence in premature ovarian failure (POF) manifestation are partially lacking. To this aim, we evaluated a large cohort of POF patients for the size and, in selected cases, for the sequence of the CGG expansion. Furthermore, the correlation between POF and X-inactivation was investigated in FRAXA families. By fluorescent PCR, 190 POF and 200 control women were sized for the CGG tract; some subjects were also characterized by sequencing and for the FMR1 activation ratio. We found a significant association (19/190, 10%, P < 1 x 10(-6)) between POF and FMR1 premutation (range 63-163 repeats) and a significant enrichment (9/190, 4.7%, P = 0.021) of POF carriers of intermediate expansions (range 41-58 repeats). Interestingly, intermediate alleles were entirely composed of CGG repeats. Furthermore, the analysis of three pairs of siblings with similar FMR1 expansions and discordant for the POF phenotype showed a direct correlation between the expression of the intermediate/premutated allele and POF manifestation. The results obtained strengthen the correlation between FMR1 expansion and POF and suggest that the manifestation of the ovarian dysfunction could be influenced both by the pattern of interruption of the CGG repeat and by X-inactivation.


Funding growth in an age of austerity.
Everyone knows that corporate growth--true growth, not just agglomeration--springs from innovation. And the common wisdom is that companies must spend lavishly on R&D if they are to innovate at all. But in these fiscally cautious times, where every line item of every budget in every company is under intense scrutiny, many organizations are doing just the opposite. They tighten their belts, subject nascent product-development programs to rigorous screening, and train R&D staffers to think in business terms so the researchers will be better able to decide whether an idea for a product or service is worth pursuing in the first place. Such efficiency measures are commendable, say authors Gary Hamel and Gary Getz. But frugality is not a growth strategy, they point out, and, in truth, there is very little correlation between corporate performance and the amount spent on innovation. Companies like Southwest, Cemex, and Shell Chemicals have shown that businesses don't have to spend a fortune on R&D to reap the benefits of innovation. To produce more growth per dollar invested, companies must produce more innovation per dollar invested. Hamel and Getz explain how businesses can dramatically improve their innovation yields. They offer these five imperatives: Increase the number of innovators among existing employees (whatever their job titles) by involving them in innovation processes and events. Focus on developing truly radical ideas--ones that change customers' expectations and behaviors and industry economics--not just incremental ideas. Look for innovation sources outside the organization, as well as inside. Increase the learning from small, low-risk experiments. And commit to long-term, consistent development efforts.


Effect of Vitamin D supplementation on body composition and cardiorespiratory fitness in overweight men-a randomized controlled trial.
Several observational studies have shown an association between vitamin D deficiency and non-skeletal major health issues including impaired cardiorespiratory fitness and adiposity. Only a few studies have examined the impact of vitamin D supplementation on these conditions and the results are ambiguous. The aim of this study was to examine the effect of vitamin D supplementation on body composition and cardiorespiratory fitness in overweight/obese men with vitamin D deficiency. This study was a prospective, placebo controlled, double blinded, randomized trial with a study period of 6 months. Forty overweight/obese men (BMI > 25 kg/m2) with vitamin D deficiency (25(OH)D ≤ 55 nmol/L) were randomized to receive either 2000 IU Cholecalciferol drops or the equivalent amount of drops of placebo. At baseline and follow up body composition and cardiorespiratory fitness were measured and blood samples were obtained. Body composition was measured using bioelectrical impedance analysis (BIA) and cardiorespiratory fitness using cardiopulmonary exercise test (CPET). The primary outcomes were changes in percentage body fat and in maximum oxygen uptake (VO2max). No statistically significant difference between the placebo and the intervention group regarding changes in percentage body fat (p = 0.54) and VO2max (p = 0.90) was observed. Moreover, there was no statistically significant difference between the groups concerning changes in BMI (p = 0.26), maximum load (p = 0.89) and oxygen uptake at anaerobic threshold (AT) (p = 0.14). We conclude that treatment with 2000 IU/d vitamin D for 6 months does not impact body composition or maximum oxygen uptake in overweight/obese men with vitamin D deficiency.


Topological dynamics and excitations in lasers and condensates with saturable gain or loss.
We classify symmetry-protected and symmetry-breaking dynamical solutions for nonlinear saturable bosonic systems that display a non-hermitian charge-conjugation symmetry, as realized in a series of recent groundbreaking experiments with lasers and exciton polaritons. In particular, we show that these systems support stable symmetry-protected modes that mirror the concept of zero-modes in topological quantum systems, as well as symmetry-protected power-oscillations with no counterpart in the linear case. In analogy to topological phases in linear systems, the number and nature of symmetry-protected solutions can change. The spectral degeneracies signalling phase transitions in linear counterparts extend to bifurcations in the nonlinear context. As bifurcations relate to qualitative changes in the linear stability against changes of the initial conditions, the symmetry-protected solutions and phase transitions can also be characterized by topological excitations, which set them apart from symmetry-breaking solutions. The stipulated symmetry appears naturally when one introduces nonlinear gain or loss into spectrally symmetric bosonic systems, as we illustrate for one-dimensional topological laser arrays with saturable gain and two-dimensional flat-band polariton condensates with density-dependent loss.


Malaria prophylaxis and self-therapy in airline crews.
The risk of malaria infection in airline crews is estimated to be 0.5 per 1,000 persons per night in areas with high levels of malaria transmission. Routine chemoprophylaxis for years is not recommended because of possible side effects. Airline crews should therefore use appropriate measures to prevent mosquito bites. In addition, they may need to carry "standby" medication with them to be used for presumptive treatment of a febrile illness if medical attention is not readily available.


From tailor-made to ready-to-wear meningococcal B vaccines: longitudinal study of a clonal meningococcal B outbreak.
Outer-membrane-vesicle vaccines for meningococcal B outbreaks are complex and time consuming to develop. We studied the use of already available vaccine to control an outbreak caused by a genetically close strain. From 2006 to 2009, all individuals younger than 20 years living in the region of Normandy, France, in which an outbreak caused by a B:14:P1.7,16 strain occurred, were eligible to receive MenBvac, a Norwegian vaccine designed 20 years earlier against a strain sharing the same serosubtype (B:15:P1.7,16). The immunogenicity (in a randomly selected cohort of 400 children aged 1-5 years), safety, and epidemiological effect of the vaccination were assessed. 26,014 individuals were eligible to receive the vaccine. Shortage of vaccine production prompted start of the campaign in the highest incidence groups (1-5 years). 16,709 (64%) received a complete vaccination schedule of whom 13,589 (81%) received a 2+1 dose schedule (week 0, week 6, and month 8). At 6 weeks after the third dose, of 235 vaccinees for whom samples were available, 206 (88%) had a seroresponse, and 108 (56 %) of 193 had a seroresponse at 15 months. These results were similar to those described for tailor-made vaccines and their homologous strain. Only previously described adverse effects occurred. The incidence of B:14:P1.7,16 cases decreased significantly in the vaccine targeted population after the primary vaccination period (from 31·6 per 100,000 to 5·9 per 100,000; p=0·001). The ready-to-wear approach is reliable if epidemic and vaccine strains are genetically close. Other meningococcal B clonal outbreaks might benefit from this strategy; and previously described outer-membrane-vesicle vaccines can be effective against various strains. French Ministry of Health.


Variations in Patterns of Utilization and Charges for the Care of Neck Pain in North Carolina, 2000 to 2009: A Statewide Claims' Data Analysis.
The purpose of the study was to compare utilization and charges generated by medical doctors (MD), doctors of chiropractic (DC) and physical therapists (PT) by provider patterns of care for the treatment of neck pain in North Carolina. This was an analysis of neck-pain-related closed claim data from the North Carolina State Health Plan for Teachers and State Employees (NCSHP) from 2000 to 2009. Data were extracted from Blue Cross Blue Shield of North Carolina for the NCSHP using ICD-9 diagnostic codes for uncomplicated neck pain (UNP) and complicated neck pain (CNP). Care patterns with single-provider types and no referrals incurred the least average charges for both UNP and CNP. When care did not include referral providers or services, for either UNP or CNP, MD care with PT was generally less expensive than MD care with DC care. However, when care involved referral providers or services, MD and PT care was on average more expensive than MD and DC care for either UNP or CNP. Risk-adjusted charges for patients in the middle quintile of risk (available 2006-2009) were lower for chiropractic patients with or without medical care or referral care to other providers. Chiropractic care alone or DC with MD care incurred appreciably fewer charges for UNP or CNP compared to MD care with or without PT care, when care included referral providers or services. This finding was reversed when care did not include referral providers or services. Risk-adjusted charges for UNP and CNP patients were lower for DC care patterns.


Processing modes and parallel processors in producing familiar keying sequences.
Recent theorizing indicates that the acquisition of movement sequence skill involves the development of several independent sequence representations at the same time. To examine this for the discrete sequence production task, participants in Experiment 1 produced a highly practiced sequence of six key presses in two conditions that allowed little preparation so that interkey intervals were slowed. Analyses of the distributions of moderately slowed interkey intervals indicated that this slowing was caused by the occasional use of two slower processing modes, that probably rely on independent sequence representations, and by reduced parallel processing in the fastest processing mode. Experiment 2 addressed the role of intention for the fast production of familiar keying sequences. It showed that the participants, who were not aware they were executing familiar sequences in a somewhat different task, had no benefits of prior practice. This suggests that the mechanisms underlying sequencing skills are not automatically activated by mere execution of familiar sequences, and that some form of top-down, intentional control remains necessary.


Effect of a Recombinant Human Soluble Thrombomodulin on Mortality in Patients With Sepsis-Associated Coagulopathy: The SCARLET Randomized Clinical Trial.
Previous research suggested that soluble human recombinant thrombomodulin may reduce mortality among patients with sepsis-associated coagulopathy. To determine the effect of human recombinant thrombomodulin vs placebo on 28-day all-cause mortality among patients with sepsis-associated coagulopathy. The SCARLET trial was a randomized, double-blind, placebo-controlled, multinational, multicenter phase 3 study conducted in intensive care units at 159 sites in 26 countries. All adult patients admitted to one of the participating intensive care units between October 2012 and March 2018 with sepsis-associated coagulopathy and concomitant cardiovascular and/or respiratory failure, defined as an international normalized ratio greater than 1.40 without other known etiology and a platelet count in the range of 30 to 150 × 109/L or a greater than 30% decrease in platelet count within 24 hours, were considered for inclusion. The final date of follow-up was February 28, 2019. Patients with sepsis-associated coagulopathy were randomized and treated with an intravenous bolus or a 15-minute infusion of thrombomodulin (0.06 mg/kg/d [maximum, 6 mg/d]; n = 395) or matching placebo (n = 405) once daily for 6 days. The primary end point was 28-day all-cause mortality. Among 816 randomized patients, 800 (mean age, 60.7 years; 437 [54.6%] men) completed the study and were included in the full analysis set. In these patients, the 28-day all-cause mortality rate was not statistically significantly different between the thrombomodulin group and the placebo group (106 of 395 patients [26.8%] vs 119 of 405 patients [29.4%], respectively; P = .32). The absolute risk difference was 2.55% (95% CI, -3.68% to 8.77%). The incidence of serious major bleeding adverse events (defined as any intracranial hemorrhage; life-threatening bleeding; or bleeding event classified as serious by the investigator, with administration of at least 1440 mL [typically 6 units] of packed red blood cells over 2 consecutive days) was 23 of 396 patients (5.8%) in the thrombomodulin group and 16 of 404 (4.0%) in the placebo group. Among patients with sepsis-associated coagulopathy, administration of a human recombinant thrombomodulin, compared with placebo, did not significantly reduce 28-day all-cause mortality. ClinicalTrials.gov Identifier: NCT01598831.


Global neurosurgery: models for international surgical education and collaboration at one university.
International collaborations between high-income (HICs) and low- and middle-income countries (LMICs) have been developed as an attempt to reduce the inequalities in surgical care around the world. In this paper the authors review different models for international surgical education and describe projects developed by the Division of Neurosurgery at the University of Toronto in this field. The authors conducted a review of models of international surgical education reported in the literature in the last 15 years. Previous publications on global neurosurgery reported by the Division of Neurosurgery at the University of Toronto were reviewed to exemplify the applications and challenges of international surgical collaborations. The most common models for international surgical education and collaboration include international surgical missions, long-term international partnerships, fellowship training models, and online surgical education. Development of such collaborations involves different challenges, including limited time availability, scarce funding/resources, sociocultural barriers, ethical challenges, and lack of organizational support. Of note, evaluation of outcomes of international surgical projects remains limited, and the development and application of assessment tools, such as the recently proposed Framework for the Assessment of International Surgical Success (FAIRNeSS), is encouraged. Actions to reduce inequality in surgical care should be implemented around the world. Different models can be used for bilateral exchange of knowledge and improvement of surgical care delivery in regions where there is poor access to surgical care. Implementation of global neurosurgery initiatives faces multiple limitations that can be ameliorated if systematic changes occur, such as the development of academic positions in global surgery, careful selection of participant centers, governmental and nongovernmental financial support, and routine application of outcome evaluation for international surgical collaborations.


1-methyladenine biosynthesis in starfish ovary: action of gonad-stimulating hormone in methylation.
Gonad-stimulating substance, a hormonal peptide released from the nervous system of starfishes, acts on the ovary to produce 1-methyladenine, an inducer of oocyte maturation. Addition of methionine to the incubation mixture of ovarian fragments and gonad-stimulating substance enhanced the production of 1-methyladenine, whereas ethionine inhibited it. Incubation of ovarian tissue with methionine alone failed to produce 1-methyladenine. Use of a radioactive label showed that methionine is a methyl donor in the biosynthesis of 1-methyladenine, suggesting that gonad-stimulating substance is involved in the methylation process.


Photo-assisted inactivation of Escherichia coli bacteria by silver functionalized titanate nanotubes, Ag/H2Ti2O5·H2O.
One-dimensional titanate nanotubes (H2Ti2O5·H2O) functionalized with silver nanoparticles (AgNPs) exhibited unique properties for the effective inactivation of the Gram-negative Escherichia coli within 45 minutes under irradiation using a 65 W halogen lamp. The pathway of the photo-assisted catalytic inactivation was examined by SEM and TEM using a reproducible biological protocol for sample preparations. The membrane integrity of the bacteria was damaged due to the oxidative stress caused by the reactive oxygen species, the bacteriostatic effect of the highly-dispersed-surface AgNPs (∼5 nm) and the sharp nanotube penetration that induced the cell death.


Impairment of rectal afferent mechanosensitivity in experimental diabetes in the rat.
Diabetes mellitus results in neuropathy of both somatic and visceral nerves. In diabetic patients with faecal incontinence, impaired rectal sensory function, manifested by a decreased sensitivity to balloon distention is common. This may contribute to unawareness of rectal filling and incontinence. There has been little study to date of visceral mechanosensation in experimental diabetes however. We hypothesized that experimental diabetes would impair mechanosensitivity in rectal afferent nerves. Diabetes was induced in rats by i.p. injection of streptozotocin. Controls were injected with citrate. In vitro recordings were performed from rectal afferent nerves innervating isolated segments of rectum. In control animals, three distinct populations of mechanosensitive fibres were identified. Low threshold fibres responded at low intensity stretch and reached a maximal firing rate at less than 10 g of stretch (11/24 units). Wide dynamic sensitivity units responded at low intensity stretch (<2 g) but encoded stimulus intensity in a linear fashion up to 20 g (12/24 units). High threshold units responded at greater than 5 g. In diabetic animals there was a near complete loss of LT units (1/19) and most (16/29) had properties similar to WD units. However, their response threshold was significantly increased. Firing rates in response to maximal distention did not change in diabetic animals. We conclude that experimental diabetes selectively affects the detection of low threshold 'physiologic' rectal distention, such as that which might occur during rectal filling, prior to defaecation.


Controlling for anthropogenically induced atmospheric variation in stable carbon isotope studies.
Increased use of stable isotope analysis to examine food-web dynamics, migration, transfer of nutrients, and behavior will likely result in expansion of stable isotope studies investigating human-induced global changes. Recent elevation of atmospheric CO2 concentration, related primarily to fossil fuel combustion, has reduced atmospheric CO2 delta13C (13C/12C), and this change in isotopic baseline has, in turn, reduced plant and animal tissue delta13C of terrestrial and aquatic organisms. Such depletion in CO2 delta13C and its effects on tissue delta13C may introduce bias into delta13C investigations, and if this variation is not controlled, may confound interpretation of results obtained from tissue samples collected over a temporal span. To control for this source of variation, we used a high-precision record of atmospheric CO2 delta13C from ice cores and direct atmospheric measurements to model modern change in CO2 delta13C. From this model, we estimated a correction factor that controls for atmospheric change; this correction reduces bias associated with changes in atmospheric isotopic baseline and facilitates comparison of tissue delta13C collected over multiple years. To exemplify the importance of accounting for atmospheric CO2 delta13C depletion, we applied the correction to a dataset of collagen delta13C obtained from mountain lion (Puma concolor) bone samples collected in California between 1893 and 1995. Before correction, in three of four ecoregions collagen delta13C decreased significantly concurrent with depletion of atmospheric CO2 delta13C (n > or = 32, P < or = 0.01). Application of the correction to collagen delta13C data removed trends from regions demonstrating significant declines, and measurement error associated with the correction did not add substantial variation to adjusted estimates. Controlling for long-term atmospheric variation and correcting tissue samples for changes in isotopic baseline facilitate analysis of samples that span a large temporal range.


Wavefront reconstruction with artificial neural networks.
In this work, a new approach, a method using artificial neural networks was applied to reconstruct the wavefront. First, the optimal structure of neural networks was found. Then, the networks were trained on both noise-free and noisy spot patterns. The results of the wavefront reconstruction with artificial neural networks were compared to those obtained through the least square fit and singular value decomposition method.


Leukocytes are primed in peripheral blood for activation during term and preterm labour.
We hypothesized that the priming and activation of maternal leukocytes in peripheral blood is a key component of parturition, and that inappropriate preterm priming of leukocytes might initiate preterm labour and delivery. The purpose of this study was to characterize peripheral blood leukocyte activation during human term and preterm labour. We obtained blood samples from pregnant women at term and preterm, both in labour and not in labour. Leukocytes were characterized according to cell subtype and cell surface marker expression. Additionally, we quantified leukocyte cytokine mRNA production, migratory ability and reactive oxygen species production of neutrophils and macrophages. We found that both term and preterm labour were associated with an increase in monocyte and neutrophil proportion or number-neutrophil migratory ability and cell surface marker expression indicating activation. Messenger RNA expression of IL-1beta and IL-8, MCP-1 and TLR-2 was also increased. We conclude that leukocytes in peripheral blood are primed in preparation for activation during term and preterm labour, and that this may contribute to the pathophysiological events of parturition. These data may lead to novel therapies and diagnostic tools for the prevention and/or diagnosis of preterm birth.


The QT interval in atrial fibrillation.
The electrocardiogram was recorded for 100 seconds in 50 patients with atrial fibrillation to determine the relations between QT intervals and both the mean and instantaneous ventricular rates. The mean ventricular rate was 94 beats per minute with a mean QT interval of 357 ms. The mean QTc, corrected beat by beat with Bazett's formula, was 444 ms--longer than reported for sinus rhythm. Between subjects, the mean QT interval was linearly related to the mean RR interval, with a slope of +21%. Within all 50 recordings there was a statistically significant correlation between QT intervals and immediately preceding RR intervals, with an average slope of +7%. This within subject QT/RR interval slope was greater at faster mean ventricular rates. In atrial fibrillation, as in sinus rhythm, the QT interval is a function of both the mean ventricular rate and the instantaneous ventricular rate, with the mean ventricular rate predominating; a simple correction of QT intervals for heart rate is therefore inadequate. Comparison of uncorrected QT intervals with those of earlier published series of people in sinus rhythm, however, suggested that atrial fibrillation is associated with prolongation of the mean QT interval.


Surfactant- and Aqueous-Foam-Driven Oil Extraction from Micropatterned Surfaces.
Liquid-infused surfaces are rough or patterned surfaces in which a lubricating fluid, such as oil, is infused, which exhibits various original properties (omniphobicity, biofouling, drag reduction). An outer flow in a confined geometry can entrain the oil trapped between the pattern of the surfaces by shearing the oil-water interface and cause the loss of the omniphobic properties of the interface. Starting from the theoretical analysis of Wexler et al. (Shear-driven failure of liquid-infused surfaces. Phys. Rev. Lett. 2015, 114, 168301), where a pure aqueous solution is the outer phase, we extend the predictions by introducing an extraction efficiency parameter α and by accounting for new dynamical effects induced by surfactants and aqueous foams. For surfactant solutions, decreasing the oil-water interfacial tension (γow) not only enhances oil extraction as expected but also modifies the dynamics of the receding oil-water interface through the variations of the receding contact angle (θ) with the capillary number (Ca), which is the ratio between the viscous and the capillary forces at the oil-water interface. For aqueous foams, the extraction dynamics are also influenced by the foam flow: oil is sheared by the thin film between the bubbles and the lubricating layer, which imposes a stronger interfacial shear compared to pure aqueous solutions. In both surfactant and foam cases, the experimental observations show the existence of nonuniform extraction dynamics related to the surfactant-induced instability of a two-fluid shear flow.


Adsorption of hexavalent chromium onto organic bentonite modified by the use of iron(III) chloride.
The adsorption of hexavalent chromium (Cr(VI)) was improved by using organic bentonite (OB) modified with iron(III) chloride. The adsorption mechanisms and characteristics of OB and organic bentonite modified by FeCl3 (FMOB) were studied by using X-ray diffraction, Fourier transform infrared spectroscopy, scanning electron microscopy, and energy dispersive X-ray spectroscopy (EDS). It was found that hydroxyl-iron replaced some of the calcium and magnesium contained in the FMOB, but no significant change in its structure was shown even though the adsorption experiments proved that FMOB had a better Cr(VI) adsorption ability compared to OB. The coated material was prepared by mixing FMOB and 4A molecular sieves in a coated pot for the adsorption experiments in the test column. The relevant results showed that the adsorption of the coated material retained its high adsorption ability and maintained that ability after desorption and regeneration, which implied a potential for further application.


The "SAPHO" syndrome: a case report of a patient with unusual bone scan findings.
The authors describe the clinical and bone scintigraphic findings of the SAPHO syndrome, which is characterized by synovitis, acne, palmoplantar pustulosis, hyperostosis, and osteitis. The case report illustrates the significance of bone scintigraphy in the diagnosis. It shows that Tc-99m MDP scanning can detect signs of arthritis not seen with other imaging methods, because the arthritis is inflammatory in nature and does not always cause bone erosion. Thus it is not visualized on plain radiographs. Knowledge of this disorder may help in the differential diagnosis of arthritis. Tc-99m MDP bone scintigraphy was used to diagnose arthritic changes. Whole-body and multiple delayed spot images were obtained in a 39-year-old diabetic, hypertensive woman who had tenderness in the plantar aspect of her heels. Swelling of the small and large joints of the feet, ankles, knees, hips, right sacroiliac joints, and shoulders was noted. She also had hydradenitis suppurativa and a history of a previous episode in which the arthritis improved after surgical treatment for the hydradenitis. All active joint lesions were visualized on the bone scan, including the arthritis, which was not detected with other imaging methods. They were all well demonstrated in the bone scintiscan. The scan findings, along with the presence of hydradenitis, led to the correct diagnosis of SAPHO syndrome. Tc-99m MDP bone scanning may be helpful in diagnosing arthritis as associated with the SAPHO syndrome.


Cyclic ADP-ribose enhances coupling between voltage-gated Ca2+ entry and intracellular Ca2+ release.
Ca2+ release from intracellular stores can be activated in neurons by influx of Ca2+ through voltage-gated Ca2+ channels. This process, called Ca2+-induced Ca2+ release, relies on the properties of the ryanodine receptor and represents a mechanism by which Ca2+ influx during neuronal activity can be amplified into large intracellular Ca2+ signals. In a differentiated neuroblastoma cell line, we show that caffeine, a pharmacological activator of the ryanodine receptor, released Ca2+ from intracellular stores in a Ca2+-dependent and ryanodine-sensitive manner. The pyridine nucleotide, cyclic ADP-ribose, thought to be an endogenous modulator of ryanodine receptors also amplified Ca2+-induced Ca2+ release in these neurons. Cyclic ADP-ribose enhanced the total cytoplasmic Ca2+ levels during controlled Ca2+ influx through voltage gated channels, in a concentration-dependent and ryanodine-sensitive manner and also increased the sensitivity with which a small amount of Ca2+ influx could trigger additional release from the ryanodine-sensitive intracellular Ca2+ stores. Single cell imaging showed that following the Ca2+ influx, cyclic ADP-ribose enhanced the spatial spread of the Ca2+ signal from the edge of the cell into its center. These powerful actions suggest a role for cyclic ADP-ribose in the functional coupling of neuronal depolarization, Ca2+ entry, and global intracellular Ca2+ signaling.


A low energy ion source for electron capture spectroscopy.
We report on the design of an ion source for the production of single and double charged Helium ions with kinetic energies in the range from 300 eV down to 5 eV. The construction is based on a commercial sputter ion gun equipped with a Wien-filter for mass/charge separation. Retardation of the ions from the ionizer potential (2 keV) takes place completely within the lens system of the sputter gun, without modification of original parts. For 15 eV He(+) ions, the design allows for beam currents up to 30 nA, limited by the space charge repulsion in the beam. For He(2 +) operation, we obtain a beam current of 320 pA at 30 eV, and 46 pA at 5 eV beam energy, respectively. In addition, operating parameters can be optimized for a significant contribution of metastable He*(+) (2s) ions.


Expression of the hyaluronan receptor, CD44S, in epithelial ovarian cancer is an independent predictor of survival.
Most ovarian carcinomas present at advanced stage, principally as the result of dissemination to peritoneal sites. Standard CD44 (CD44S) is the principal receptor for hyaluronic acid, and in vitro and animal studies have suggested that the attachment of ovarian carcinoma cells to the peritoneal mesothelium involves the interaction between CD44S on ovarian carcinoma cells and hyaluronic acid on mesothelial surfaces. We, therefore, analyzed a series of ovarian carcinomas for the expression of CD44S by immunohistochemistry to see whether expression of this receptor by tumor cells correlated with clinicopathological factors and measures of patient outcome. Fifty-six fixed, paraffin-embedded primary epithelial ovarian tumors were immunostained with antibody to CD44S. Membrane staining was considered positive, and results were correlated with stage, grade, age, histology, and survival. Twenty-two (39%) tumors were positive for CD44S. There was no correlation between CD44 expression and histological type, grade, age, or stage. However, CD44 expression was significantly associated with survival in both univariate (P = 0.003) and multivariate (P = 0.006) analyses. These results support a role for CD44S expression in the spread of ovarian epithelial cancer and suggest that expression of this molecule is a significant independent predictor of survival in women with this disease.


NMR diffusion measurements in complex mixtures using constant-time-HSQC-IDOSY and computer-optimized spectral aliasing for high resolution in the carbon dimension.
A new 3D pulse sequence for NMR diffusion measurements in complex mixtures is presented. It is based on the constant-time (CT) HSQC experiment and combines diffusion delay with the carbon evolution time. This combination has great potential to obtain high resolution in the carbon dimension. When using classical sampling of the carbon dimension, maximal resolution would require a large number of time increments, leading to unrealistically long acquisition times. The application of computer-optimized spectral aliasing allows one to reduce the number of time increments and the total acquisition time by 1-2 orders of magnitude by taking advantage of the information content of 1D carbon spectra, HSQC experiments, or both. With the new CT-HSQC-IDOSY experiment, the diffusion rates of the six anomers present in a 0.1 M D2O solution of glucose, maltose, and maltotriose could be obtained at natural abundance in 8 h with standard deviations below 5%.


Modulation of DNA damage and alteration of gene expression during aflatoxicosis via dietary supplementation of Spirulina (Arthrospira) and Whey protein concentrate.
Spirulina (SPN) and Whey protein (WPC) are being touted as functional foods with a number of health benefits. SPN is blue green algae while WPC is a protein complex derived from milk and both have strong antioxidant activity and provoke a free radical scavenging enzyme system. The aim of the present study was to evaluate the antioxidant potentials of SPN and WPC to regulate the alteration of genes' expression and counteract oxidative stress in rats during aflatoxecosis. Eighty male Sprague-Dawley rats were divided into eight groups, which included the control group, the group fed with aflatoxins (AFs)-contaminated diet (2.5 mg/kg diet) for 30 day, the group treated orally with WPC (300 mg/kg b.w.), the group treated orally with SPN (50 mg/kg b.w), the group treated orally with WPC plus SPN and the groups fed with AFs-contaminated diet and treated orally with WPC, SPN and/or WPC. Oxidative stress markers and gene expression were assayed in liver and testis and the damage of DNA was evaluated by DNA fragmentation and micronucleus tests. The results demonstrated that supplementation of SPN and/or WPC reduced the oxidative stress induced by AFs as indicated by decreased lipid peroxidation level, increased glutathione content and up-regulated PHGPx gene expression. Both agents succeed to inhibit DNA damage as indicated by the down-regulation of Fas gene expression, and decreased the percentage of DNA fragmentation and micronucleated erythrocytes. Moreover, WPC was found to be effective than SPN and the combined treatment was more effective than the single treatment. It could be concluded that both SPN and WPC induced a protective action and regulated the alteration of genes expression induced by AFs; however, the combined treatment may be useful than the single treatment.


Nanotechnology: emerging tools for biology and medicine.
Historically, biomedical research has been based on two paradigms. First, measurements of biological behaviors have been based on bulk assays that average over large populations. Second, these behaviors have then been crudely perturbed by systemic administration of therapeutic treatments. Nanotechnology has the potential to transform these paradigms by enabling exquisite structures comparable in size with biomolecules as well as unprecedented chemical and physical functionality at small length scales. Here, we review nanotechnology-based approaches for precisely measuring and perturbing living systems. Remarkably, nanotechnology can be used to characterize single molecules or cells at extraordinarily high throughput and deliver therapeutic payloads to specific locations as well as exhibit dynamic biomimetic behavior. These advances enable multimodal interfaces that may yield unexpected insights into systems biology as well as new therapeutic strategies for personalized medicine.


A Benchmark Open-Source Implementation of COSMO-SAC.
The COSMO-SAC modeling approach has found wide application in science as well as in a range of industries due to its good predictive capabilities. While other models for liquid phases, as for example UNIFAC, are in general more accurate than COSMO-SAC, these models typically contain many adjustable parameters and can be limited in their applicability. In contrast, the COSMO-SAC model only contains a few universal parameters and subdivides the molecular surface area into charged segments that interact with each other. In recent years, additional improvements to the construction of the sigma profiles and evaluation of activity coefficients have been made. In this work, we present a comprehensive description of how to postprocess the results of a COSMO calculation through to the evaluation of thermodynamic properties. We also assembled a large database of COSMO files, consisting of 2261 compounds, freely available to academic and noncommercial users. We especially focus on the documentation of the implementation and provide the optimized source code in C++, wrappers in Python, and sample sigma profiles calculated from each approach, as well as tests and validation results. The misunderstandings in the literature relating to COSMO-SAC are described and corrected. The computational efficiency of the implementation is demonstrated.


Touch influences visual perception with a tight orientation-tuning.
Stimuli from different sensory modalities are thought to be processed initially in distinct unisensory brain areas prior to convergence in multisensory areas. However, signals in one modality can influence the processing of signals from other modalities and recent studies suggest this cross-modal influence may occur early on, even in 'unisensory' areas. Some recent psychophysical studies have shown specific cross-modal effects between touch and vision during binocular rivalry, but these cannot completely rule out a response bias. To test for genuine cross-modal integration of haptic and visual signals, we investigated whether congruent haptic input could influence visual contrast sensitivity compared to incongruent haptic input in three psychophysical experiments using a two-interval, two-alternative forced-choice method to eliminate response bias. The initial experiment demonstrated that contrast thresholds for a visual grating were lower when exploring a haptic grating that shared the same orientation compared to an orthogonal orientation. Two subsequent experiments mapped the orientation and spatial frequency tunings for the congruent haptic facilitation of vision, finding a clear orientation tuning effect but not a spatial frequency tuning. In addition to an increased contrast sensitivity for iso-oriented visual-haptic gratings, we found a significant loss of sensitivity for orthogonally oriented visual-haptic gratings. We conclude that the tactile influence on vision is a result of a tactile input to orientation-tuned visual areas.


Validation study of the modified injection technique for internal mammary sentinel lymph node biopsy in breast cancer.
According to the hypothesis of internal mammary sentinel lymph node (IM-SLN) lymphatic drainage pattern, a modified radiotracer injection technique (periareolar intraparenchyma, high volume, and ultrasonographic guidance) was established. To verify the accuracy of the hypothesis and validate the modified radiotracer injection technique and to observe whether the lymphatic drainage of the whole breast parenchyma could reach to the same IM-SLN, different tracers were injected into different locations of the breast. The validation study results showed that the correlation and the agreement of the radiotracer and the fluorescence tracer are significant (case-base, r s =0.808, P<0.001; Kappa =0.79, P<0.001). It proved that the lymphatic drainage from different location of the breast (the primary tumor, the subareolar plexus) reached the same IM-SLNs and the hypothesis of IM-SLN lymphatic drainage pattern (ie, IM-SLN receives lymphatic drainage from not only the primary tumor area, but also the entire breast parenchyma). In other words, it validated the accuracy of our modified radiotracer injection technique.


Effect of stretching stress on gene transcription related to early-phase differentiation in rat periodontal ligament cells.
Mechanical stress such as occlusal and orthodontic loading has been suggested to induce a homeostatic and regenerative response in periodontal ligament (PDL), but the underlying mechanism remains to be clarified. The purpose of this study was to investigate expression of mRNAs encoding proteins involved in osteogenesis and homeostasis by PDL cells following application of tensile stress and characterize the relationship between such expression and the regenerative and homeostatic functions of the PDL. PDL cells were obtained from rats and stretched by 9% or 18% at a frequency of 6 cycles/min for 12 hr to 5 days in a FX-4000T™ culture system. After stretching, expression of mRNAs encoding collagen type I (Col-I), alkaline phosphatase (ALP), bone morphogenetic protein-2 (BMP-2), bone morphogenetic protein-4 (BMP-4), heat shock protein 70 (HSP70) and basic fibroblast growth factor (bFGF) was investigated. The highest levels of Col-I, ALP and BMP-2 mRNA expression occurred at 12 hr, while those of BMP-4 and HSP70 occurred at 1 day and 5 days, respectively. Expression levels of Col-I, ALP, BMP-2, BMP-4 and HSP70 increased magnitude-dependently with stretching force in the stretching groups. In contrast, expression of bFGF mRNA showed statistically significant reduction in both stretching groups, with the largest reduction seen in the 9% stretching group (p<0.01). These results suggest that stretching of PDL cells provokes significant increases in expression of factors promoting osteogenic differentiation and HSP70, which protects PDL cells undergoing mechanical stress and contributes to maintenance of PDL homeostasis. However, expression of bFGF was restrained. Reduced expression of bFGF mRNA suggested that there was an optimum magnitude of stretching force for increasing expression.


The Effect of Primary Surgery in Patients with De Novo Stage IV Breast Cancer with Bone Metastasis Only (Protocol BOMET MF 14-01): A Multi-Center, Prospective Registry Study.
More evidence shows that primary surgery for de novo metastatic breast cancer (BC) prolongs overall survival (OS) in selected cases. The aim of this study was to evaluate the role of locoregional treatment (LRT) in BC patients with de novo stage IV bone only metastasis (BOM). The prospective, multicenter registry study BOMET MF14-01 was initiated in May 2014. Patients with de novo stage IV BOM BC were divided into two groups: those receiving systemic treatment (ST group) and those receiving LRT (LRT group). Patients who received LRT were further divided into two groups: ST after LRT (LRT + ST group) and ST before LRT (ST + LRT group). We included 505 patients in this study; 240 (47.5%) patients in the ST group and 265 (52.5%) in the LRT group. One hundred and thirteen patients (26.3%) died in the 34-month median follow-up, 85 (35.4%) in the ST group and 28 (10.5%) in LRT group. Local progression was observed in 39 (16.2%) of the patients in the ST group and 18 (6.7%) in the LRT group (p = 0.001). Hazard of death was 60% lower in the LRT group compared with the ST group (HR 0.40, 95% CI 0.30-0.54, p < 0.0001). In this prospectively maintained registry study, we found that LRT prolonged survival and decreased locoregional recurrence in the median 3-year follow-up. Timing of primary breast surgery either at diagnosis or after ST provided a survival benefit similar to ST alone in de novo stage IV BOM BC patients.


Relative production of tumour necrosis factor alpha and interleukin 10 in adult respiratory distress syndrome.
The adult respiratory distress syndrome (ARDS) may be regarded as an example of an uncontrolled or excessive inflammatory response in which tumour necrosis factor alpha (TNF-alpha) has been proposed to play a central role. Interleukin 10 (IL-10) has been identified as an important regulator of this response. The potential role for IL-10 in this context was investigated by measuring the relative production of IL-10 and TNF-alpha protein in the plasma, bronchoalveolar lavage (BAL) fluid, and alveolar macrophage culture supernatants of patients with, or at risk of developing, ARDS. Twenty six patients were studied from three groups at risk of or with ARDS: sepsis (n = 12), multiple trauma (n = 8), and perforated bowel (n = 6). Ten patients had ARDS. Bronchoalveolar lavage and venepuncture were performed within 24 hours of arrival on the intensive therapy unit or of diagnosis of ARDS. IL-10 and TNF-alpha protein were detected in the plasma, BAL fluid, and alveolar macrophage supernatants by sandwich enzyme linked immunoabsorbent assays. The median IL-10 concentrations in the plasma and BAL fluid of patients with ARDS were significantly lower than the concentrations detectable in the plasma (median difference-17.5, 95% CI -52.4 to 1.31, p < 0.05) and BAL fluid of at risk patients (median difference -32.1, 95% CI -47.5 to 2.3, p < 0.05). There was a tendency towards enhanced concentrations of TNF-alpha detectable in the alveolar macrophage supernatants and the BAL fluid of patients with ARDS compared with at risk patients, although this did not reach statistical significance. No difference was observed in the plasma concentrations of TNF-alpha between the two groups. The ratios of TNF-alpha to IL-10 protein in the BAL fluid of patients with ARDS and at risk patients were 3.52 and 0.85, respectively (median difference 1.44, 95% CI 0.07 to 5.01, p < 0.01). There was no difference in alveolar macrophage production of IL-10 between the two groups. This study highlights the potential importance of the pro-inflammatory versus the anti-inflammatory imbalance in ARDS which may be reflected by the ratio of IL-10 and TNF-alpha in the lung.


Next Generation Sequencing and ALS: known genes, different phenotyphes.
Amyotrophic lateral sclerosis (ALS) is fatal neurodegenerative disease clinically characterized by upper and lower motor neuron dysfunction resulting in rapidly progressive paralysis and death from respiratory failure. Most cases appear to be sporadic, but 5-10 % of cases have a family history of the disease, and over the last decade, identification of mutations in about 20 genes predisposing to these disorders has provided the means to better understand their pathogenesis. Next Generation sequencing (NGS) is an advanced high-throughput DNA sequencing technology which have rapidly contributed to an acceleration in the discovery of genetic risk factors for both familial and sporadic neurological and neurodegenerative diseases. These strategies allowed to rapidly identify disease-associated variants and genetic risk factors for both familial (fALS) and sporadic ALS (sALS), strongly contributing to the knowledge of the genetic architecture of ALS. Moreover, as the number of ALS genes grows, many of the proteins they encode are in intracellular processes shared with other known diseases, suggesting an overlapping of clinical and phatological features between different diseases. To emphasize this concept, the review focuses on genes coding for Valosin-containing protein (VPC) and two Heterogeneous nuclear RNA-binding proteins (HNRNPA1 and hnRNPA2B1), recently idefied through NGS, where different mutations have been associated in both ALS and other neurological and neurodegenerative diseases.


The impact of individualized interaction on the quality of life of elderly dependent on care as a result of dementia: a study with a pre-post design.
The aim was to assess the impact of a one-to-one 30-min individualized interaction per day on the behavior and quality of life of care-dependent residents with dementia. In a pre-/post-test study, 15 care-dependent residents with dementia (mean age 88.8 years, 86.7% women) were included. Resident behavior was measured using video observation and quality of life using Qualidem. Health care professionals (n = 13) and direct relatives (n = 4) were interviewed about the effect of the intervention. The effect of the intervention was analyzed using the Friedman analysis of variance. The video observation showed that maintaining eye contact, touching, responding to speaking, tracking observable stimuli and asking questions about the activity significantly increased during the intervention. These findings were supported by interviews with nurses who described experiences of making human-to-human contact with the residents. No significant overall changes were found in quality of life. These findings were partially supported by interviews with health care professionals and relatives as some perceived effects beyond the 30-min intervention. Interaction offered on a one-to-one basis tailored to individual preferences significantly improved positive interactive behavior of care-dependent residents with dementia during the intervention. Surveys revealed no significant overall effect of the intervention. The interviews indicated there might be effects beyond the intervention for some residents.


Compounding medications in a rural setting: an interprofessional perspective.
Interprofessional learning (IPL) which focuses on the pharmacist's role in specialty practices as part of a multidisciplinary health care team has not been explored. This study aimed to determine health care students' understanding of the role of the pharmacist in compounding medications to optimize health outcomes for patients in rural and remote health care services. Four workshops followed by focus group interviews were conducted with undergraduate pharmacy, medical, nursing, physiotherapy, dentistry, Aboriginal public health, and speech pathology students (n=15). After an introductory lecture, students working in multidisciplinary teams undertook to compound three products. Focus groups were held at the end of the compounding workshops to explore students' understanding and perceptions of these compounding activities. Thematic analysis was undertaken on the qualitative data obtained from the focus groups. Student participants responded positively both to the opportunity to undertake a compounding exercise and being part of an interprofessional team, perceiving benefit for their future rural and remote health practice. Four major themes emerged from the qualitative analysis: improved knowledge and understanding; application to practice; interprofessional collaboration; and rural, remote, and Indigenous context. Students acknowledged that the workshops improved their understanding of the role of the pharmacist in compounding and how they, as part of a multidisciplinary team, could deliver better health outcomes for patients with special needs, especially in a rural and remote context. This study highlights that workshops of this nature have a role to play in developing collaborative interprofessional practice and increasing awareness of pharmaceutical services among undergraduate health students. However, further evidence is needed to assess whether positive perceptions of specialty practice IPL workshops will translate into improved patient outcomes in practice.


Molecular archaeoparasitology identifies cultural changes in the Medieval Hanseatic trading centre of Lübeck.
Throughout history, humans have been afflicted by parasitic worms, and eggs are readily detected in archaeological deposits. This study integrated parasitological and ancient DNA methods with a large sample set dating between Neolithic and Early Modern periods to explore the utility of molecular archaeoparasitology as a new approach to study the past. Molecular analyses provided unequivocal species-level parasite identification and revealed location-specific epidemiological signatures. Faecal-oral transmitted nematodes (Ascaris lumbricoides and Trichuris trichiura) were ubiquitous across time and space. By contrast, high numbers of food-associated cestodes (Diphyllobothrium latum and Taenia saginata) were restricted to medieval Lübeck. The presence of these cestodes and changes in their prevalence at approximately 1300 CE indicate substantial alterations in diet or parasite availability. Trichuris trichiura ITS-1 sequences grouped into two clades; one ubiquitous and one restricted to medieval Lübeck and Bristol. The high sequence diversity of T.tITS-1 detected in Lübeck is consistent with its importance as a Hanseatic trading centre. Collectively, these results introduce molecular archaeoparasitology as an artefact-independent source of historical evidence.


Incentive motivational salience and the human brain.
In this paper the concept of incentive motivational salience is briefly described, pioneering studies on the subject of the mesolimbic motivational system are reviewed, and studies we have been involved in conducting which elaborate on this subject are discussed. In particular, we aim to show that the mesolimbic motivational system is recruited as a reaction to primary and secondary reinforcers as a function of salience, that is independent of valence. Furthermore, studies showing that both psychological and pharmacological interventions can affect the function of the mesolimbic motivational system and how its' dysfunction is related to psychopathological phenomena with an emphasis on psychosis are discussed.


Insight into the prebiotic concept: lessons from an exploratory, double blind intervention study with inulin-type fructans in obese women.
To highlight the contribution of the gut microbiota to the modulation of host metabolism by dietary inulin-type fructans (ITF prebiotics) in obese women. A double blind, placebo controlled, intervention study was performed with 30 obese women treated with ITF prebiotics (inulin/oligofructose 50/50 mix; n=15) or placebo (maltodextrin; n=15) for 3 months (16 g/day). Blood, faeces and urine sampling, oral glucose tolerance test, homeostasis model assessment and impedancemetry were performed before and after treatment. The gut microbial composition in faeces was analysed by phylogenetic microarray and qPCR analysis of 16S rDNA. Plasma and urine metabolic profiles were analysed by 1H-NMR spectroscopy. Treatment with ITF prebiotics, but not the placebo, led to an increase in Bifidobacterium and Faecalibacterium prausnitzii; both bacteria negatively correlated with serum lipopolysaccharide levels. ITF prebiotics also decreased Bacteroides intestinalis, Bacteroides vulgatus and Propionibacterium, an effect associated with a slight decrease in fat mass and with plasma lactate and phosphatidylcholine levels. No clear treatment clustering could be detected for gut microbial analysis or plasma and urine metabolomic profile analyses. However, ITF prebiotics led to subtle changes in the gut microbiota that may importantly impact on several key metabolites implicated in obesity and/or diabetes. ITF prebiotics selectively changed the gut microbiota composition in obese women, leading to modest changes in host metabolism, as suggested by the correlation between some bacterial species and metabolic endotoxaemia or metabolomic signatures.


The roles of O-linked β-N-acetylglucosamine in cardiovascular physiology and disease.
More than 1,000 proteins of the nucleus, cytoplasm, and mitochondria are dynamically modified by O-linked β-N-acetylglucosamine (O-GlcNAc), an essential post-translational modification of metazoans. O-GlcNAc, which modifies Ser/Thr residues, is thought to regulate protein function in a manner analogous to protein phosphorylation and, on a subset of proteins, appears to have a reciprocal relationship with phosphorylation. Like phosphorylation, O-GlcNAc levels change dynamically in response to numerous signals including hyperglycemia and cellular injury. Recent data suggests that O-GlcNAc appears to be a key regulator of the cellular stress response, the augmentation of which is protective in models of acute vascular injury, trauma hemorrhage, and ischemia-reperfusion injury. In contrast to these studies, O-GlcNAc has also been implicated in the development of hypertension and type II diabetes, leading to vascular and cardiac dysfunction. Here we summarize the current understanding of the roles of O-GlcNAc in the heart and vasculature.


Effects of aggressive cholesterol lowering and low-dose anticoagulation on clinical and angiographic outcomes in patients with diabetes: the Post Coronary Artery Bypass Graft Trial.
Diabetic patients have greater risk for coronary heart disease (CHD) events after coronary artery bypass graft (CABG) surgery than nondiabetic patients. The Post CABG trial studied the effects of aggressive cholesterol lowering and low-dose anticoagulation in diabetic patients compared with nondiabetic patients. A double-blind, randomized clinical trial in 1,351 patients (1-11 years after CABG), the Post CABG trial consisted of two interventions (aggressive cholesterol-lowering versus moderate lowering and low-dose warfarin versus placebo) on angiographic end points. Angiographic changes in saphenous vein graft conduits 4.3 years after entry were compared in 116 diabetic and 1,235 nondiabetic patients. Seven clinical centers participated in the trial, as well as the National Institutes of Health project office (National Heart, Lung, and Blood Institute), the coordinating center (Maryland Medical Research Institute), and the Angiogram Reading Center (University of Minnesota). Baseline characteristics of the diabetic patients differed from the nondiabetic patients in the following ways: percentage of women participants, 15 vs. 7%, P = 0.002; mean baseline weight, 87.4 vs. 82.8 kg, P = 0.006; mean BMI, 29.5 vs. 27.6 kg/m2, P = 0.0002; mean systolic blood pressure, 141.7 vs. 133.6, P < 0.0001; mean triglyceride concentrations, 2.09 vs. 1.77 mmol/l, P < 0.0001; and mean HDL cholesterol concentrations, 0.93 vs. 1.02 mmol, P = 0.0001. The percentage of clinical events was higher in diabetic than nondiabetic patients (20.6 vs. 13.4, P = 0.033) and angiographic outcomes were not different. The benefits of aggressive cholesterol lowering were comparable in diabetic and nondiabetic patients for the angiographic end points. Warfarin use was not associated with clinical or angiographic benefit. Diabetic patients in the Post CABG trial had more CHD risk factors at study entry and higher clinical event rates during the study than nondiabetic patients. The benefits of aggressive cholesterol lowering in diabetic patients were comparable to those in nondiabetic patients for both angiographic and clinical end points. The small number of diabetic patients provided limited power to detect significant differences between diabetic and nondiabetic patients or between diabetic patients in the aggressive versus moderate cholesterol treatment strategies.


How to Bond Zirconia: The APC Concept.
Zirconia has become one of the most popular materials in dentistry. New high-translucent zirconia ceramics have favorable optical properties and can be applied as monolithic full-contour restorations in various clinical indications for posterior and anterior teeth. However, having reliable cementation protocols is fundamental for clinical success of indirect ceramic dental restorations, including those made from zirconia materials. Resin bonding supports ceramic restorations and is necessary for onlays, laminate veneers, and resinbonded fixed dental prostheses. The APC zirconia-bonding concept is based on decades of research on how to achieve high and long-term durable bond strengths to high-strength ceramics. It includes three practical steps: (A) airparticle abrasion, (P) zirconia primer, and (C) adhesive composite resin. This article discusses the history and development of high-translucent zirconia and explains the necessity for proper cementation. The rationale and science behind a simplified zirconia-bonding concept is explained and illustrated with a clinical case presentation.


Reversible epithelial to mesenchymal transition and acquired resistance to sunitinib in patients with renal cell carcinoma: evidence from a xenograft study.
Tyrosine kinase inhibitors (TKI) targeting angiogenesis via inhibition of the vascular endothelial growth factor pathway have changed the medical management of metastatic renal cell carcinoma. Although treatment with TKIs has shown clinical benefit, these drugs will eventually fail patients. The potential mechanisms of resistance to TKIs are poorly understood. To address this question, we obtained an excisional biopsy of a skin metastasis from a patient with clear cell renal carcinoma who initially had a response to sunitinib and eventually progressed with therapy. Tumor pieces were grafted s.c. in athymic nude mice. Established xenografts were treated with sunitinib. Tumor size, microvascular density, and pericyte coverage were determined. Plasma as well as tissue levels for sunitinib were assessed. A tumor-derived cell line was established and assessed in vitro for potential direct antitumor effects of sunitinib. To our surprise, xenografts from the patient who progressed on sunitinib regained sensitivity to the drug. At a dose of 40 mg/kg, sunitinib caused regression of the subcutaneous tumors. Histology showed a marked reduction in microvascular density and pericyte dysfunction. More interestingly, histologic examination of the original skin metastasis revealed evidence of epithelial to mesenchymal transition, whereas the xenografts showed reversion to the clear cell phenotype. In vitro studies showed no inhibitory effect on tumor cell growth at pharmacologically relevant concentrations. In conclusion, the histologic examination in this xenograft study suggests that reversible epithelial to mesenchymal transition may be associated with acquired tumor resistance to TKIs in patients with clear cell renal carcinoma.


DNA bending by the TrpI protein of Pseudomonas aeruginosa.
TrpI protein, the activator of transcription of the trpBA operon of fluorescent pseudomonads, bends the DNA when it forms either of two well-characterized complexes with the trpBA regulatory region. In complex 1, with TrpI bound only to its strong binding site (site I), the calculated bending angle is 65 to 67 degrees and the center of bending is in the middle of site I. In complex 2, which is required for activation of the trpBA promoter, with TrpI bound both to site I and to the weaker site II, the bending angle is increased to 89 to 90 degrees and the center of bending is at the site I-site II boundary. Indoleglycerol phosphate (InGP), which strongly stimulates formation of complex 2 and is required for activation, does not affect the bending angle of either complex. However, a mutation (-10C/11C) shown previously to affect activation has a small but detectable effect on bending, reducing the calculated bending angle to 83 to 86 degrees. These results suggest a way that DNA bending and InGP may be important for activation.


Antimicrobial susceptibility of cerebrospinal isolates from patients with meningitis.
Str. pneumoniae isolates were susceptible to penicillin, all to also ofloxacin and chloramphenicol and cefotaxim and 39 (100%) to cotrimoxazol. Concerning S. aureus, all isolates 22 were susceptible to oxacillin and chloramphenicol, and 21 also to cotrimoxazol. All N. meningitidis isolates but one-10 of all were susceptible to penicillin, all to cefotaxim, chloramphenicol and cotrimoxazol. All H.influenzae isolates were susceptible to ampicillin and chloramphenicol, as well as to ofloxacin and cotrimoxazol. Those surprisingly high susceptibilities to rather "old" antibiotics may be explained by low antibiotic consumption, accessibility and therefore low usage which is a key promoter of resistance both in community and hospital.


Association of Waist-Hip Ratio to Sudden Cardiac Death and Severe Coronary Atherosclerosis in Medicolegal Autopsies.
Various modifiable and nonmodifiable risk factors, such as abdominal obesity, are known to affect the development of atherosclerotic cardiovascular disease and subsequent sudden cardiac death (SCD). The waist-hip ratio is a surrogate marker of visceral obesity that has been shown in various studies to be a better predictor of cardiovascular risk than the body mass index (BMI), a measurement of generalized obesity. Waist-hip ratio was measured prospectively on medicolegal autopsies performed for 1 year, in addition to standard measurements of BMI and heart weight, and histologic determination of severe coronary atherosclerosis (SCA, coronary artery diameter stenosis >75%). Logistic modeling was performed to determine any association between WHR, BMI, cardiovascular disease risk factors, heart weight, and SCD or SCA. Waist-hip ratio was not shown to be statistically significantly associated with either SCD (P = 0.68) or SCA (P = 0.14). Body mass index was shown to be significantly associated with SCA (P < 0.001), and heart weight was shown to be significantly associated with both SCD and SCA (P < 0.001, both). Waist-hip ratio, as a surrogate marker of central obesity and increased risk of atherosclerotic cardiovascular disease, is shown not to be statistically significantly associated with either SCD or SCA in postmortem cases.


Penetration of bevacizumab through the retina after intravitreal injection in the monkey.
The penetration of intravitreally injected bevacizumab in its commercial formulation (Avastin; Roche, Grenzach, Germany) through the retina was studied, to determine whether a full-length antibody would be able to penetrate the retina as easily as an antibody fragment. Six cynomolgus monkeys (Macaca fascicularis) were used in this study. Two compositions of intravitreal injection into the right eyes were performed: one with commercial Avastin (group 1, four animals) and the other one with commercial Avastin labeled with 125I (group 2, one animal). The animals in group 1 were killed 1, 4, 7, or 14 days after the injection for subsequent histologic analysis of the eyes by immunohistochemistry, and the animal in group 2 was killed 7 days after injection for autoradiography and electron microscopy. Funduscopy was performed before the injection and at several time points thereafter. Moreover, blood samples were collected at different time points from the group-2 animal. The sixth animal remained untreated and served as the control. No pathologic changes were obvious in the funduscopic images within the time of the experiment. Bevacizumab immunoreactivity was found in the choroid and the inner layers of the retina as early as 1 day after the injection and spread to the outer layers and the choroid within the following days, in particular to photoreceptors and blood vessels. Avastin labeled with 125I showed radioactivity in blood serum 1 day after the intravitreal injection and remained relatively stable until day 7. The results clearly show that the bevacizumab molecule can penetrate the retina and is also transported into the retinal pigment epithelium, the choroid and, in particular, into photoreceptor outer segments after intravitreal injection of Avastin. Active transport mechanisms seem to be involved.


Partial deletion of an antithrombin III allele in a kindred with a type 1 deficiency.
This report details the precise mapping of a partially deleted human antithrombin III (AT-III) allele, found in a kindred with an inherited type 1 AT-III deficiency. Using truncated AT-III probes generated by polymerase chain reaction (PCR) amplification from a full-length AT-III cDNA, as well as other genomic probes specific for the 5' upstream region of the AT-III gene, we were able to characterize a partial deletion on an AT-III allele encompassing exons 1 and 2 of the AT-III gene, and a region 5' to the coding sequences. The absence of the 5' upstream region in the affected AT-III allele was confirmed directly by the PCR amplification of a 1.5-kb polymorphic fragment of genomic DNA samples from family members. The precise determination of the 5' breakpoint of the affected allele was made possible by two different approaches: (1) subcloning plus biotin capture PCR, or (2) inverse PCR. This allowed us to confirm the mapping of the deletion obtained by Southern analysis; to show that the 3' region of the mutant AT-III allele, including exons 3 to 7, was intact; and to sequence approximately 0.7 kb upstream to the breakpoint in the mutant allele. Furthermore, PCR amplification of the region of the breakpoint provided unique products detectable only in affected members of this kindred. The breakpoint in the partially deleted allele is 480 bp upstream from the 5' boundary of exon 3. No significant homology was found between the 0.7-kb sequence upstream to the breakpoint of the mutant allele and known human sequences.


A three-dimensional transient mixed hybrid finite element model for superabsorbent polymers with strain-dependent permeability.
A hydrogel is a cross-linked polymer network with water as solvent. Industrially widely used superabsorbent polymers (SAP) are partially neutralized sodium polyacrylate hydrogels. The extremely large degree of swelling is one of the most distinctive characteristics of such hydrogels, as the volume increase can be about 30 times its original volume when exposed to physiological solution. The large deformation resulting from the swelling demands careful numerical treatment. In this work, we present a biphasic continuum-level swelling model using the mixed hybrid finite element method (MHFEM) in three dimensions. The hydraulic permeability is highly dependent on the swelling ratio, resulting in values that are orders of magnitude apart from each other. The property of the local mass conservation of MHFEM contributes to a more accurate calculation of the deformation as the permeability across the swelling gel in a transient state is highly non-uniform. We show that the proposed model is able to simulate the free swelling of a random-shaped gel and the squeezing of fluid out of a swollen gel. Finally, we make use of the proposed numerical model to study the onset of surface instability in transient swelling.


Global pattern and controls of biological nitrogen fixation under nutrient enrichment: A meta-analysis.
Biological nitrogen (N) fixation (BNF), an important source of N in terrestrial ecosystems, plays a critical role in terrestrial nutrient cycling and net primary productivity. Currently, large uncertainty exists regarding how nutrient availability regulates terrestrial BNF and the drivers responsible for this process. We conducted a global meta-analysis of terrestrial BNF in response to N, phosphorus (P), and micronutrient (Micro) addition across different biomes (i.e, tropical/subtropical forest, savanna, temperate forest, grassland, boreal forest, and tundra) and explored whether the BNF responses were affected by fertilization regimes (nutrient-addition rates, duration, and total load) and environmental factors (mean annual temperature [MAT], mean annual precipitation [MAP], and N deposition). The results showed that N addition inhibited terrestrial BNF (by 19.0% (95% confidence interval [CI]: 17.7%-20.3%); hereafter), Micro addition stimulated terrestrial BNF (30.4% [25.7%-35.3%]), and P addition had an inconsistent effect on terrestrial BNF, i.e., inhibiting free-living N fixation (7.5% [4.4%-10.6%]) and stimulating symbiotic N fixation (85.5% [25.8%-158.7%]). Furthermore, the response ratios (i.e., effect sizes) of BNF to nutrient addition were smaller in low-latitude (<30°) biomes (8.5%-36.9%) than in mid-/high-latitude (≥30°) biomes (32.9%-61.3%), and the sensitivity (defined as the absolute value of response ratios) of BNF to nutrients in mid-/high-latitude biomes decreased with decreasing latitude (p ≤ 0.009; linear/logarithmic regression models). Fertilization regimes did not affect this phenomenon (p > 0.05), but environmental factors did affect it (p < 0.001) because MAT, MAP, and N deposition accounted for 5%-14%, 10%-32%, and 7%-18% of the variance in the BNF response ratios in cold (MAT < 15°C), low-rainfall (MAP < 2,500 mm), and low-N-deposition (<7 kg ha-1 year-1 ) biomes, respectively. Overall, our meta-analysis depicts a global pattern of nutrient impacts on terrestrial BNF and indicates that certain types of global change (i.e., warming, elevated precipitation and N deposition) may reduce the sensitivity of BNF in response to nutrient enrichment in mid-/high-latitude biomes.


HDAC4 does not act as a protein deacetylase in the postnatal murine brain in vivo.
Reversible protein acetylation provides a central mechanism for controlling gene expression and cellular signaling events. It is governed by the antagonistic commitment of two enzymes families: the histone acetyltransferases (HATs) and the histone deacetylases (HDACs). HDAC4, like its class IIa counterparts, is a potent transcriptional repressor through interactions with tissue specific transcription factors via its N-terminal domain. Whilst the lysine deacetylase activity of the class IIa HDACs is much less potent than that of the class I enzymes, HDAC4 has been reported to influence protein deacetylation through its interaction with HDAC3. To investigate the influence of HDAC4 on protein acetylation we employed the immunoaffinity-based AcetylScan proteomic method. We identified many proteins known to be modified by acetylation, but found that the absence of HDAC4 had no effect on the acetylation profile of the murine neonate brain. This is consistent with the biochemical data suggesting that HDAC4 may not function as a lysine deacetylase, but these in vivo data do not support the previous report showing that the enzymatic activity of HDAC3 might be modified by its interaction with HDAC4. To complement this work, we used Affymetrix arrays to investigate the effect of HDAC4 knock-out on the transcriptional profile of the postnatal murine brain. There was no effect on global transcription, consistent with the absence of a differential histone acetylation profile. Validation of the array data by Taq-man qPCR indicated that only protamine 1 and Igfbp6 mRNA levels were increased by more than one-fold and only Calml4 was decreased. The lack of a major effect on the transcriptional profile is consistent with the cytoplasmic location of HDAC4 in the P3 murine brain.


Iron Deficiency among Jamaican Adolescents.
To raise awareness of significant iron deficiency anaemia occurring in Jamaican secondary school students. Haematological screening of students in the fifth and sixth forms of 14 secondary schools in the parishes of Manchester and Clarendon, Jamaica, was done. Samples were subject to haemoglobin electrophoresis, examination of haematological indices, and haemoglobin, alpha 2 (HbA2) levels where indicated. Of 13 172 students with normal haemoglobin (AA) genotype aged 15-19 years, haemoglobin levels below 10 g/dL occurred in 0.36% of males and in 3.79% females. These subjects had low mean red cell volumes, low mean cell haemoglobin and high red cell distribution width, characteristic of iron deficiency, which was confirmed by dramatic increases in haemoglobin level following iron supplementation. Most revealed classic symptoms, histories of poor diets and pica, which generally resolved on iron supplementation. Iron deficiency, even in the absence of anaemia, is known to limit physical and mental functions and may impair intellectual performance in these high school students. Significant anaemia could be detected by incorporating a blood test into the school medical assessments performed on entry to secondary schools. There is a need for simple oral iron medications to be available at health centres.


Practical aspects of implementing three-dimensional tomography inversion for volumetric flame imaging.
Instantaneous three-dimensional (3D) measurements have been long desired to resolve the spatial structures of turbulent flows and flame. Previous efforts have demonstrated tomography as a promising technique to enable such measurements. To facilitate the practical application, this work investigated four practical aspects for implementing 3D tomographic under the context of volumetric combustion diagnostics. Both numerical simulations and controlled experiments were performed to study: (1) the termination criteria of the inversion algorithm; (2) the effects of regularization and the determination of the optimal regularization factor; (3) the effects of a number of views; and (4) the impact of the resolution of the projection measurements. The results obtained have illustrated the effects of these practical aspects on the accuracy and spatial resolution of volumetric tomography. Furthermore, all these aspects are related to the complexity and implementing cost (both hardware cost and computational cost). Therefore, the results obtained in this work are expected to be valuable for the design and implementation of practical 3D diagnostics.


An embedded system for the automated generation of labeled plant images to enable machine learning applications in agriculture.
A lack of sufficient training data, both in terms of variety and quantity, is often the bottleneck in the development of machine learning (ML) applications in any domain. For agricultural applications, ML-based models designed to perform tasks such as autonomous plant classification will typically be coupled to just one or perhaps a few plant species. As a consequence, each crop-specific task is very likely to require its own specialized training data, and the question of how to serve this need for data now often overshadows the more routine exercise of actually training such models. To tackle this problem, we have developed an embedded robotic system to automatically generate and label large datasets of plant images for ML applications in agriculture. The system can image plants from virtually any angle, thereby ensuring a wide variety of data; and with an imaging rate of up to one image per second, it can produce lableled datasets on the scale of thousands to tens of thousands of images per day. As such, this system offers an important alternative to time- and cost-intensive methods of manual generation and labeling. Furthermore, the use of a uniform background made of blue keying fabric enables additional image processing techniques such as background replacement and image segementation. It also helps in the training process, essentially forcing the model to focus on the plant features and eliminating random correlations. To demonstrate the capabilities of our system, we generated a dataset of over 34,000 labeled images, with which we trained an ML-model to distinguish grasses from non-grasses in test data from a variety of sources. We now plan to generate much larger datasets of Canadian crop plants and weeds that will be made publicly available in the hope of further enabling ML applications in the agriculture sector.


The growth and survival of Mycobacterium smegmatis is enhanced by co-metabolism of atmospheric H2.
The soil bacterium Mycobacterium smegmatis is able to scavenge the trace concentrations of H2 present in the atmosphere, but the physiological function and importance of this activity is not understood. We have shown that atmospheric H2 oxidation in this organism depends on two phylogenetically and kinetically distinct high-affinity hydrogenases, Hyd1 (MSMEG_2262-2263) and Hyd2 (MSMEG_2720-2719). In this study, we explored the effect of deleting Hyd2 on cellular physiology by comparing the viability, energetics, transcriptomes, and metabolomes of wild-type vs. Δhyd2 cells. The long-term survival of the Δhyd2 mutant was significantly reduced compared to the wild-type. The mutant additionally grew less efficiently in a range of conditions, most notably during metabolism of short-chain fatty acids; there was a twofold reduction in growth rate and growth yield of the Δhyd2 strain when acetate served as the sole carbon source. Hyd1 compensated for loss of Hyd2 when cells were grown in a high H2 atmosphere. Analysis of cellular parameters showed that Hyd2 was not necessary to generate the membrane potential, maintain intracellular pH homeostasis, or sustain redox balance. However, microarray analysis indicated that Δhyd2 cells were starved for reductant and compensated by rewiring central metabolism; transcripts encoding proteins responsible for oxidative decarboxylation pathways, the urea cycle, and ABC transporter-mediated import were significantly more abundant in the Δhyd2 mutant. Metabolome profiling consistently revealed an increase in intracellular amino acids in the Δhyd2 mutant. We propose that atmospheric H2 oxidation has two major roles in mycobacterial cells: to generate reductant during mixotrophic growth and to sustain the respiratory chain during dormancy.


Physical Vein Models to Quantify the Flow Performance of Sclerosing Foams.
Foam sclerotherapy is clinically employed to treat varicose veins. It involves intravenous injection of foamed surfactant agents causing endothelial wall damage and vessel shrinkage, leading to subsequent neovascularization. Foam production methods used clinically include manual techniques, such as the Double Syringe System (DSS) and Tessari (TSS) methods. Pre-clinical in-vitro studies are conducted to characterize the performance of sclerosing agents; however, the experimental models used often do not replicate physiologically relevant physical and biological conditions. In this study, physical vein models (PVMs) were developed and employed for the first time to characterize the flow behavior of sclerosing foams. PVMs were fabricated in polydimethylsiloxane (PDMS) by replica molding, and were designed to mimic qualitative geometrical characteristics of veins. Foam behavior was investigated as a function of different physical variables, namely (i) geometry of the vein model (i.e., physiological vs. varicose vein), (ii) foam production technique, and (iii) flow rate of a blood surrogate. The experimental set-up consisted of a PVM positioned on an inclined platform, a syringe pump to control the flow rate of a blood substitute, and a pressure transducer. The static pressure of the blood surrogate at the PVM inlet was measured upon foam administration. The recorded pressure-time curves were analyzed to quantify metrics of foam behavior, with a particular focus on foam expansion and degradation dynamics. Results showed that DSS and TSS foams had similar expansion rate in the physiological PVM, whilst DSS foam had lower expansion rate in the varicose PVM compared to TSS foam. The degradation rate of DSS foam was lower than TSS foam, in both model architectures. Moreover, the background flow rate had a significant effect on foam behavior, enhancing foam displacement rate in both types of PVM.


High School FLASH Sexual Health Education Curriculum: LGBTQ Inclusivity Strategies Reduce Homophobia and Transphobia.
Homophobic and transphobic beliefs that lead to bias-based harassment remain a critical concern for young people in the USA. The aim of the present study was to examine the impact of an inclusive comprehensive sex education program (High School FLASH) on homophobic and transphobic beliefs. Data from this study come from a randomized controlled trial that evaluated the impact of High School FLASH on students' sexual behaviors and related outcomes with 20 schools in two U.S. regions (Midwest and South). Following the baseline survey, the 20 schools were randomly assigned to receive FLASH or a comparison curriculum. Ninth and 10th grade students completed follow-up surveys 3 and 12 months after the instructional period. We examined changes in homophobic beliefs using multilevel linear regression models in the full sample and two sub-groups: straight cisgender young people versus those who identified as not straight or cisgender. Mean scores on the homophobic and transphobic beliefs scale were statistically significantly lower among young people receiving FLASH relative to the comparison at both the 3- and 12-month timepoints (p-values for adjusted mean differences were < 0.01, n = 1357 and 1275, respectively). Specifically, FLASH's positive impact on reducing homophobic and transphobic beliefs was statistically significant for straight and cisgender youth at both survey follow-ups (p < 0.01, n = 1144 and p = 0.05, n = 1078, respectively); the effects for the LGBTQ sub-group reached statistical significance at only the final follow-up (p = 0.01, n = 197). Our results show that carefully designed, inclusive comprehensive sexual health education programs like High School FLASH can play a role in promoting better school climates for all youth by reducing beliefs that may lead to bullying, violence, and victimization.


Targeting the pregnane X receptor using microbial metabolite mimicry.
The human PXR (pregnane X receptor), a master regulator of drug metabolism, has essential roles in intestinal homeostasis and abrogating inflammation. Existing PXR ligands have substantial off-target toxicity. Based on prior work that established microbial (indole) metabolites as PXR ligands, we proposed microbial metabolite mimicry as a novel strategy for drug discovery that allows exploiting previously unexplored parts of chemical space. Here, we report functionalized indole derivatives as first-in-class non-cytotoxic PXR agonists as a proof of concept for microbial metabolite mimicry. The lead compound, FKK6 (Felix Kopp Kortagere 6), binds directly to PXR protein in solution, induces PXR-specific target gene expression in cells, human organoids, and mice. FKK6 significantly represses pro-inflammatory cytokine production cells and abrogates inflammation in mice expressing the human PXR gene. The development of FKK6 demonstrates for the first time that microbial metabolite mimicry is a viable strategy for drug discovery and opens the door to underexploited regions of chemical space.


Cannabis for the Management of Pain: Assessment of Safety Study (COMPASS).
Cannabis is widely used as a self-management strategy by patients with a wide range of symptoms and diseases including chronic non-cancer pain. The safety of cannabis use for medical purposes has not been systematically evaluated. We conducted a prospective cohort study to describe safety issues among individuals with chronic non-cancer pain. A standardized herbal cannabis product (12.5% tetrahydrocannabinol) was dispensed to eligible individuals for a 1-year period; controls were individuals with chronic pain from the same clinics who were not cannabis users. The primary outcome consisted of serious adverse events and non-serious adverse events. Secondary safety outcomes included pulmonary and neurocognitive function and standard hematology, biochemistry, renal, liver, and endocrine function. Secondary efficacy parameters included pain and other symptoms, mood, and quality of life. Two hundred and fifteen individuals with chronic pain were recruited to the cannabis group (141 current users and 58 ex-users) and 216 controls (chronic pain but no current cannabis use) from 7 clinics across Canada. The median daily cannabis dose was 2.5 g/d. There was no difference in risk of serious adverse events (adjusted incidence rate ratio = 1.08, 95% confidence interval = .57-2.04) between groups. Medical cannabis users were at increased risk of non-serious adverse events (adjusted incidence rate ratio = 1.73, 95% confidence interval = 1.41-2.13); most were mild to moderate. There were no differences in secondary safety assessments. Quality-controlled herbal cannabis, when used by patients with experience of cannabis use as part of a monitored treatment program over 1 year, appears to have a reasonable safety profile. Longer-term monitoring for functional outcomes is needed. The study was registered with www.controlled-trials.com (ISRCTN19449752). This study evaluated the safety of cannabis use by patients with chronic pain over 1 year. The study found that there was a higher rate of adverse events among cannabis users compared with controls but not for serious adverse events at an average dose of 2.5 g herbal cannabis per day.


Structural basis of RNA cap modification by SARS-CoV-2.
The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the causative agent of COVID-19 illness, has caused millions of infections worldwide. In SARS coronaviruses, the non-structural protein 16 (nsp16), in conjunction with nsp10, methylates the 5'-end of virally encoded mRNAs to mimic cellular mRNAs, thus protecting the virus from host innate immune restriction. We report here the high-resolution structure of a ternary complex of SARS-CoV-2 nsp16 and nsp10 in the presence of cognate RNA substrate analogue and methyl donor, S-adenosyl methionine (SAM). The nsp16/nsp10 heterodimer is captured in the act of 2'-O methylation of the ribose sugar of the first nucleotide of SARS-CoV-2 mRNA. We observe large conformational changes associated with substrate binding as the enzyme transitions from a binary to a ternary state. This induced fit model provides mechanistic insights into the 2'-O methylation of the viral mRNA cap. We also discover a distant (25 Å) ligand-binding site unique to SARS-CoV-2, which can alternatively be targeted, in addition to RNA cap and SAM pockets, for antiviral development.


Procentriole assembly revealed by cryo-electron tomography.
Centrosomes are cellular organelles that have a major role in the spatial organisation of the microtubule network. The centrosome is comprised of two centrioles that duplicate only once during the cell cycle, generating a procentriole from each mature centriole. Despite the essential roles of centrosomes, the detailed structural mechanisms involved in centriole duplication remain largely unknown. Here, we describe human procentriole assembly using cryo-electron tomography. In centrosomes, isolated from human lymphoblasts, we observed that each one of the nine microtubule triplets grows independently around a periodic central structure. The proximal end of the A-microtubule is capped by a conical structure and the B- and C-microtubules elongate bidirectionally from its wall. These observations suggest that the gamma tubulin ring complex (gamma-TuRC) has a fundamental role in procentriole formation by nucleating the A-microtubule that acts as a template for B-microtubule elongation that, in turn, supports C-microtubule growth. This study provides new insights into the initial structural events involved in procentriole assembly and establishes the basis for determining the molecular mechanisms of centriole duplication on the nanometric scale.